ABSTRACT Postoperative complications such as delirium represent an immense public health challenge that will continue to intensify as life-expectancy and the number of surgeries during a lifespan continue to increase. Despite efforts to optimize preventive measures, the incidence of postoperative delirium can affect up to 87% of older adults, depending on age and surgical procedures, and remains without an effective treatment. Patients with mild- cognitive impairment (MCI) are most at risk for developing postoperative delirium. Even routine surgical procedures such as common knee replacement or fracture repair, may result in life-threatening outcomes including increased risk for long-term cognitive dysfunction. Thus, new therapeutic strategies are urgently needed. Our long-term goal is to define novel Juvenile Protective Factors (JPFs) derived from intestinal microbiota and to determine their capacity to protect against the development and progression of aging-related neurodegenerative and perioperative disorders. The objective here is to compare molecular signatures in intestinal microbiome samples from healthy juveniles and patients at risk for developing postoperative delirium, which includes older adults and adults with MCI. Our central hypothesis is that juvenile-associated intestinal microbiota generate JPFs that confer resiliency to age-associated neuroinflammation and postoperative delirium. This hypothesis will be tested by pursuing 2 specific aims: 1) analyze the bacterial communities and their molecular signatures in juvenile, aged, and MCI fecal samples; and 2) determine the functional impact of different human microbiota communities on postoperative neuroinflammation and delirium-like behavior. The feasibility of collecting and analyzing these large datasets and models has been established in our laboratories by a unique translational team. Our preliminary data provide evidence that specific metabolites, known to protect against neuronal death, are enriched in feces from juvenile mice. In this innovative approach, we will transplant fecal samples from donor human juvenile, elderly, or MCI patients into germ-free recipient mice in a clinically-relevant surgical mouse model of postoperative neuroinflammation and delirium-like behaviors. Our rationale for the proposed research is that successful completion will demonstrate a novel link between aging-related changes in microbiota and resiliency to postoperative neuroinflammation and cognitive deficits. This work will be significant by improving our understanding of how intestinal microbiota control fundamental brain pathology (ie, neuroinflammation and cogntive decline) that may reveal a unique approach to effective treatment for perioperative neurologic complications.